This application is relevant to U.S. Ser. No. 09/526,143, filed Mar. 15, 2000, now U.S. Pat. No. 6,320,050.
Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J, 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides an amide selected from the group consisting of a compound of the formula: 
wherein R1 and R2 are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, R3is lower alkyl having from 2 to 4 carbon atoms or a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R4 is xe2x80x94C(O)NHR5, or is R6, which is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; with said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, xe2x80x94(CH2)nxe2x80x94OR9, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR10, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94R11, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94OR12, xe2x80x94(CH2)nxe2x80x94NHR13; n is 0, 1, 2, 3 or 4; R7, R8, R9, R10, R11, R12, R13 are independently hydrogen or lower alkyl, R5 is hydrogen, lower alkyl, lower alkenyl, hydroxy lower alkyl, halo lower alkyl, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR7, xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR8, X is oxygen, sulfur, sulfonyl, or carbonyl; the * indicates an asymmetric carbon atom; and its pharmaceutically acceptable salts.
Preferably, the compound of formula I is in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon, shown except in the case where X is carbonyl (Cxe2x95x90O), when the preferred enantiomer is xe2x80x9cSxe2x80x9d.
The compounds of formula I have been found to activate glucokinase. Glucokinase activators are useful in the treatment of type II diabetes.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
In one embodiment, this invention provides amides of formula I, comprising compounds of formulae II and III as follows: 
wherein R1 and R2 are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkylthio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, (preferably hydrogen, halo, lower alkyl sulfonyl, or perfluoro lower alkyl sulfonyl) R3 is a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R5 is lower alkyl, X is oxygen, sulfur, sulfonyl or carbonyl, the * indicates an asymmetric carbon atom and 
wherein R1 and R2 are independently hydrogen, halo, cyano, nitro, lower alkylthio, perfluoro lower alkyl thio, lower alkyl sulfonyl, or perfluoro-lower alkyl sulfonyl, (preferably hydrogen, halo, lower alkyl sulfonyl, or perfluoro lower alkyl sulfonyl) R3 is a 5 to 7-membered ring which is cycloalkyl, cycloalkenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur, R6 is an unsubstituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amide group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom, X is oxygen, sulfur, sulfonyl or carbonyl, and the * indicates an asymmetric carbon atom
Preferably, the compounds of formulae II and III are in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown except in the case where X is carbonyl (Cxe2x95x90O), when the preferred enantiomer is xe2x80x9cSxe2x80x9d. The pharmaceutically acceptable salts of each amide of this invention are compounds of this invention.
In preferred amides of formula II, R1 and R2 are independently halo or lower alkyl sulfonyl, R3 is a 5 to 7-membered ring which is cyclopentyl, cyclohexyl, cyclohexenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur (preferably oxygen) (Compound A).
In certain amides of Compound A, R5 is methyl, and X is oxygen. More preferably R1; and R2 are independently chloro or methyl sulfonyl (which means R1 and R2 may each be chloro or methyl sulfonyl, or one is chloro while the other is methyl sulfonyl) (compound A-1). Examples of such compounds where R1 and R2 are chloro are
1-[cyclopentyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea,
1-[cyclohexyloxy-(3,4-dichloro-phenyl)-acetyl]-3 -methyl-urea,
1-[(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea and
1-[(3,4-dichloro-phenyl)-(tetrahydro-pyran-4-yloxy)-acetyl]-3-methyl-urea.
Examples of the amides of Compound A-1 where R1 is choro and R2 is methyl sulfonyl are
1-[(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetyl]-3 -methyl-urea and
1[(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetyl]-3 -methyl-urea.
In preferred amides of formula III, R1 and R2 are independently halo or lower alkyl sulfonyl, R3 is a 5 to 7-membered ring which is cyclopentyl, cyclohexyl, cyclohexenyl, or heterocycloalkyl having one heteroatom selected from oxygen and sulfur (preferably oxygen)(Compound B). Preferably R6 is thiazolyl or pyridinyl, and R1 and R2 are independently chloro or methyl sulfonyl (Compound B-1).
In certain amides of Compound B-1, it is preferred that X is oxygen, especially when R1 and R2 are chloro and R6 is thiazolyl or pyridinyl. Examples of such compounds where R6 is thiazolyl are:
2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-N-thiazol-2-yl-acetamide,
2-Cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide,
2-Cyclohexyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide, and
2-(Cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide.
An example of such compounds where R6 is pyridinyl is 2-Cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-acetamide.
In another amide of Compound B-1 where X is oxygen, R1 is chloro and R2 is methyl sulfonyl. Examples of such compounds are:
2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxy-N-thiazol-2-yl-acetamide and
2-(3-chloro-4-methanesulfonyl-phenyl)-2-(cyclohex-2-enyloxy-N-(4,5-dihydro-thiazol-2-yl-acetamide.
In yet another amide of Compound B-1, X is sulfur, sulfonyl or carbonyl, R1 and R2 are chloro, and R3 is cyclopentyl. Examples of such compounds are:
3-Cyclopentyl-2-(3,4-dichloro-phenyl)-3-oxo-N-thiazol-2-yl-propionamide,
2-Cyclopentanesulfonyl-2-(3,4-dichloro-phenyl)-N -hiazol-2-yl-acetamide and
2-Cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide.
For each compound described above, each variable which is specifically indicated may be combined with any other variable of formula I or may be combined with any one or more specifically indicated variable.
In the compound of formula I, the * indicates the asymmetric carbon. The compound of formula I may be present either as a racemate or in the xe2x80x9cRxe2x80x9d configuration at except in the case where X is carbonyl (Cxe2x95x90O), when the preferred enantiomer is xe2x80x9cSxe2x80x9d. the asymmetric carbon shown. The xe2x80x9cRxe2x80x9d enantiomers are preferred, Where R3 is asymmetric an additional chiral center at the ring carbon connected with X is generated. At this center the compounds of formula I may be present as a racemate or in the xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d configuration.
As used herein, the term xe2x80x9chalogenxe2x80x9d and the term xe2x80x9chaloxe2x80x9d, unless otherwise stated, designate all four halogens, i.e. fluorine, chlorine, bromine and iodine. Preferred halogens are chlorine and bromine, most preferred is chlorine.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl. As used herein, xe2x80x9clower alkyl sulfonylxe2x80x9d means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group. Similarly xe2x80x9cperfluoro-lower alkyl sulfonylxe2x80x9d means a perfluoro-lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group.
As used herein, xe2x80x9clower alkyl thioxe2x80x9d means a lower alkyl group as defined above where a thio group is bound to the rest of the molecule. Similarly xe2x80x9cperfluoro-lower alkyl thioxe2x80x9d means a perfluoro-lower alkyl group as defined above where a thio group is bound to the rest of the molecule.
As used herein, xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferably from 5 to 7 carbon atoms. Preferred cycloalkyls are cyclopentyl and cyclohexyl. As used herein, xe2x80x9ccycloalkenylxe2x80x9d means a cycloalkyl ring having from 3 to 10, and preferably from 5 to 7 carbon atoms, where one of the bonds between the ring carbons is unsaturated. As used herein, xe2x80x9cheterocycloalkylxe2x80x9d means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferably from 5 to 7 carbon atoms, and having a heteroatom which may be oxygen or sulfur. It is preferred to have a single heteroatom, preferably oxygen.
As used herein, the term xe2x80x9clower alkenylxe2x80x9d denotes an alkylene group having from 2 to 6 carbon atoms with a double bond located between any two adjacent carbons of the group. Preferred lower alkenyl groups are allyl and crotyl.
The variable X may be an oxygen or sulfur (i.e. xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94) or sulfonyl or carbonyl (i.e. SO2 or Cxe2x95x90O).
The heteroaromatic ring can be an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur and connected by a ring carbon to the amide group shown. The heteroaromatic ring has at least one nitrogen atom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be sulfur, oxygen or nitrogen. Certain preferred rings contain a nitrogen atom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon or adjacent to said first heteroatom. The heteroaromatic rings are connected via a ring carbon atom to the amide group. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage cannot contain any substituent. Heteroaromatic rings include, for example, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl (preferably 1,3,4-, 1,2,3-, 1,2,4-), triazinyl (preferably 1,3,5-, 1,2,4-), thiazolyl, oxazolyl, and imidazolyl. Preferred rings are thiazolyl for example 4 or 5-halothiazolyl, 4 or 5 lower alkyl thiazolyl, pyridinyl, and pyrimidinyl, for example 2-lower alkyl pyrimidinyl. Most preferred are thiazolyl or pyridinyl.
Preferable compounds in accordance with the present invention are compounds of above formula I, wherein R5 is lower alkyl, preferably methyl. In one embodiment, preferable heteroaromaric ring R1 is thiazolyl; in another embodiment, preferable heteroaromatic ring R6 is pyridinyl. In one embodiment, preferable R1 and R2 are independently halo (preferably chloro) or lower alkyl sulfonyl (preferably methyl sulfonyl); in another embodiment, R1 and R2 are chloro; in still another embodiment, R1 is chloro and R2 is methyl sulfonyl. Preferable residue R3 is cyclopentyl, cyclohexyl, cyclohexenyl, with cyclopentyl being preferred, or a six-membered heterocycloalkyl having one heteroatom selected from oxygen and sulfur, with oxygen being preferred. In one embodiment, X is oxygen; in another embodiment, X is sulfur, sulfonyl or carbonyl.
Most preferable compounds in accordance with the present invention are:
1-[cyclopentyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea,
1-[cyclohexyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea,
1-[(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea,
1-[(3,4-dichloro-phenyl)-(tetrahydro-pyran-4-yloxy)-acetyl]-3-methyl-urea,
1-[(3-chloro-4-methanesulfonyl-phenyl)-cyclopentyloxy-acetyl-3-methyl-urea,
1-[(3-chloro-4-methanesulfonyl-phenyl)-(cyclohex-2-enyloxy)-acetyl]-3-methyl-urea,
2-(3,4-dichloro-phenyl)-2-(tetrahydro-pyran-4-yloxy)-N-thiazol-2-yl-acetamide,
2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide,
2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2- yl-acetamide,
2-cyclohex-2-enyloxy-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide,
2-(cyclopentyloxy)-2-(3,4-dichloro-phenyl)-N- pyridin-2-yl-acetamide,
2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxy-N-thiazol-2-yl-acetamide,
2-(3-chloro-4-methanesulfonyl-phenyl)-2-(cyclohex-2-enyloxy-N-(4,5-dihydro-thiazol-2-yl-acetamide,
3-cyclopentyl-2-(3,4-dichloro-phenyl)-3-oxo-N-thiazol-2-yl-propionamide,
2-cyclopentanesulfonyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide and
2-cyclopentylsulfanyl-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques. This invention includes the pharmaceutically acceptable salt of each compound of formula I.
The compound of formula I can be prepared by the following Reaction Schemes which follow.
During the course of the reactions, the various functional groups such as the free carboxylic acid or hydroxy groups will be protected via conventional hydrolyzable ester or ether protecting groups. As used herein the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective hydroxyl or carboxyl group. Exemplary ester groups useful for the protection of a hydroxyl group are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxcyclic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Example of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxcyclic acid anhydrides, e.g. succinic anhydride. Suitable ether protecting groups for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroyl substituted methyl ethers such as benzyl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
Exemplary ester groups useful for the protection of carboxylic acid groups are those derived from lower alkanols or substituted or unsubstituted benzyl alcohols. The choice of ester functions used is well known to those of ordinary skill in the art of organic chemistry. For example, the ester functions most readily cleaved under basic hydrolysis are those derived from lower primary alcohols such as methyl, ethyl, and the like. Ester functions derived from secondary or tertiary alcohols are more readily cleaved under acidic conditions, for example tertiary butyl or diphenylmethyl esters. Benzyl esters are particularly useful for the protection of carboxylic acid functions in compounds that are stable to the hydrogenolytic conditions that can be used to remove the protecting group.
The term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups such as those utilized in peptide synthesis, particularly the carbamates. Particularly preferred amino protecting groups in this class are t-butoxycarbonyl (BOC), carbobenzyloxy (CBZ), and 9-fluorenylmethoxy-carbonyl (FMOC) moieties. Each of these protecting groups is readily removed under reaction conditions that do not affect the others. For example FMOC and CBZ protecting groups are stable to the acidic conditions used to remove BOC groups and other acid labile moieties. CBZ groups can be removed by hydrogenolysis in the presence of FMOC and BOC protecting groups, while the FMOC moiety is particularly labile in the presence of secondary cyclic amines, conditions under which BOC and CBZ groups are unaffected. 
Reaction Scheme II outlines the preparation of the phenylpyruvic acid ester of formula 6, from which compounds of formula I where Xxe2x95x90O, S, or DO2 can be prepared. The compounds of formula 6 are accessible from the corresponding phenyl acetic acids of structure 3 or substituted benzenes of structure 1 as outlined in Reaction Scheme II ( see for example, Anderson, J. C. and Smith, S. C. Syn. Lett., 1990, 107; Davis, F. A., Haque, M. S., et al.,J. Org. Chem, 1986, 51, 2402; Tanaka, M.; Kobayashi, T. and Sakakura, T.; Angew. Chem. Int. Ed. Engl, 1984, 23, 518; Murahashi, S. and Naota, T., Synthesis, 1993, 433). The method to prepare the pyruvates of structure 6 via the xcex1-hydroxy phenylacetic acids of structure 7 may be considered a general procedure regardless of the nature of the substituents R1 and R2, with the proviso that these substituents are protected during the process with suitable protecting groups if required. The alternative procedure, the preparation of the pyruvates of structure 6 by an electrophilic substitution reaction on the substituted benzenes of structure 10 under Friedel-Crafts, is useful for certain selected R1 and R2 which can be identified by the skilled chemist.
In the compounds of formula 3 wherein one of R1 and R2 is nitro, chloro, bromo, or iodo and the other is hydrogen, either the carboxylic acids 3 or their lower alkyl esters 4 (Ra=lower alkyl) are commercially available. In those cases where the available starting acids of formula 3 or the commercially available potential progenitors 1, 3, or 5 do not carry the desired substituents, that is, R1 and R2 do not fall within the scope of the all definitions listed herein for R1 and R2, the substituents of the available starting materials can be manipulated by any of the commonly known methods to interconvert aromatic substituents to ultimately lead to the desired substitution pattern in the phenylpyruvates of structure 6 i.e., for all definitions of R1 and R2. In cases where only the carboxylic acids of structure 3 are available, they can be converted to the corresponding esters 4 of lower alkyl alcohols using any conventional esterification methods. All the substituent interconversion reactions discussed hereto forward are carried out on lower alkyl esters of the compounds of formula 4.
The amino substituted compounds of formula 4 which in turn can be obtained from the corresponding NO2 compound which can be diazotized to yield the corresponding diazonium compound, which in situ can be reacted with the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for example, Baleja, J. D. Synth. Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem. Comm. 1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. Labelled Compd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164), or alkaline earth metal cyanide, to yield corresponding compounds of formula 4, where one of the substituents is lower alkyl thio, perfluoro-lower alkyl thio, or cyano, and the other is hydrogen. If desired, the lower alkyl thio or perfluoro-lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compounds of formula 4. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
In the compounds of formula 3 wherein both of R1 and R2 are chloro or fluoro, the carboxylic acids 4 or the corresponding lower alkyl esters of structure 4 are commercially available. In cases where only the carboxylic acids are available, they can be converted to the corresponding esters of lower alkyl alcohols using any conventional esterification method. As shown in Reaction Scheme II, to produce the compound of formula 3 where both R1 and R2 are nitro, 3,4-dinitrotoluene (R1=R2xe2x95x90NO2) can be used as starting material. This can be converted to the corresponding 3,4-dinitrobenzoic acid 2. Any conventional method of converting an aryl methyl group to the corresponding benzoic acid can be utilized to effect this conversion (see for example, Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M, Synthesis, 1991, 871). The benzoic acids of structure 2 can be homologated to the corresponding phenyl acetic acids of structure 3 by the well-known Arndt Eistert method.
The compounds of formula 4b where both R1 and R2 substituents are amino can be obtained from the corresponding di-nitro compound of formula 4a, described above. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The compound of formula 4b where both R1 and R2 are amine groups can be used to prepare the corresponding compound of formula 4d where both R1 and R2 are iodo, bromo, chloro, or fluoro via the diazotization reaction intermediate 4c described before. Any conventional method of converting amino group to an iodo or bromo group (see for example, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943, 351) can be utilized to effect this conversion.
If it is desired to produce compounds of formula 4e,f, where both R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio groups, the compound of formula 4b where R1 and R2 are amino can be used as starting material. Any conventional method of converting an aryl amino group to aryl thioalkyl group can be utilized to effect this conversion. If it is desired to produce compounds of formula 4g,h where R1and R2 are lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds of formula 4e,f where R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio can be used as starting material. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion.
If it is desired to produce compounds of formula 4i, where both R1 and R2 are cyano groups, the compound of formula 4b can be used as starting material. Any conventional method used to convert an amino group to cyano group can be utilized to effect this conversion.
The carboxylic acids of formula 3 where one of R1 and R2 is nitro and the other is halo (for example chloro) are known from the literature (see for 4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid, Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be converted to the corresponding lower alkyl esters 4m,n using any conventional esterification methods. Thus, if it is desired to produce the compound of formula 4 where one of R1 and R2 is nitro and the other is lower alkyl thio (4o,p) or perfluoro-lower alkyl thio (4q,r), the corresponding compound where one of R1 and R2 is nitro and the other is chloro can be used as starting material. In this reaction, any conventional method of nucleophilic displacement of aromatic chlorine group with a lower alkyl thiol can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J. Chem. Res. -S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W, US patent, U.S. Pat. No. 5,169,951). Once the compounds of formula 4 where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio are available, they can be converted to the corresponding compounds of formula 4 wherein one of R1 and R2 is nitro and the other is lower alkyl sulfonyl (4s,t) or perfluoro-lower alkyl sulfonyl (4u,v) using conventional oxidation procedures.
If it is desired to produce compounds of formula 4aa-ad where one of R1 and R2 is lower alkyl thio and the other is per fluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is amino and the other is lower alkylthio (4w,x) or per fluoro-lower alkylthio (4y,z) can be used as starting materials. Any conventional method of diazotizing an aromatic amino group and reacting it in situ with the desired lower alkyl thiol or per tluoroalkyl thiol can be utilized to effect this conversion.
If it is desired to produce compounds of formula 4 where one of R1 and R2 is lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl, (4ae-4ah) the corresponding compounds (4aa-ad) where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether group to the corresponding sulfone group can be utilized to effect this conversion.
If it is desired to produce compounds of formula 4 where one of R1 and R2 is halo and the other is lower alkyl thio (4ai,aj) or perfluoro-lower alkyl thio (4ak,al), the corresponding compounds where one of R1 and R2 is amino and the other is lower alkyl thio (4w,x) or perfluoro-lower alkyl thio (4y,z) can be used as starting materials. Any conventional method of diazotizing an aromatic amino group and conversion of it in situ to an aromatic halide can be utilized to effect this conversion.
If it is desired to produce compounds of formula 4 where one of R1 and R2 is cyano, and the other is halo, (4aq, 4ar), the corresponding compounds of formula (4as, 4at) where one of R1 and R2 is nitro, and the other is amino can be used as starting materials. This transformation can be achieved via conversion of amino group of compounds of formula (4as, 4at) to corresponding halo compounds (4au, 4av), which in turn further can be transformed to the compounds of formula (4aq, 4ar).
If it is desired to produce compounds of formula 4 where one of R1 and R2 is cyano, and the other is lower alkylthio or lower perfluoro lower alkylthio (4ba-4be), the corresponding compounds of formula 4as, 4at can be used as starting material. Any conventional means of converting an amino group to a thioalkyl group can be used to affect this conversion.
If it is desired to produce compounds of formula 4 where one of R1 and R2 is cyano and the other is lower alkylsulfonyl or perfluoro-loweralkylsulfonyl (4bf-4bi), the corresponding compounds of formula (4ba-4be) can be used as starting material. Any conventional means of converting a thio ether to the corresponding sulfone can be used to affect this conversion.
If it is desired to produce compounds of formula 4 where one of R1 and R2 is halo and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, (4am-4ap) the corresponding compounds where one of R1 and R2 is halo and the other is lower alkyl thio (4ai,aj) or perfluoro-lower alkyl thio (4ak,al) can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether to the corresponding sulfone can be utilized to effect this conversion.
In cases where one or both of R1 or R2 is an amino group in compounds of structure 6, the amino groups are protected with a conventional amino protecting group, before further transformations are carried out.
Preparation of compounds of formula I where X is O or S is outlined in Reaction Scheme I. The pyruvate esters of formula 6 are transformed to the corresponding aryl sulfonyl hydrazones of formula 9 by reacting the pyruvate esters with the appropriate sulfonylhydrazide derivative. This reaction is conveniently carried out by conventional aryl sulfonyl hydrazide condensation reaction conditions, for example by refluxing a solution of the pyruvate ester 6 and p-toluenesulfonyl hydrazide in an inert solvent, preferably an aromatic hydrocarbon, for example benzene or toluene, preferably toluene. The reaction may be performed in an apparatus designed such that the refluxing solvent, which contains the azeotroped reaction byproduct, water, to pass though a water removing agent, such as molecular sieves, before returning to the reaction flask. In this manner, the hydrazone forming reaction may be accelerated and driven to completion. The p-toluenesulfonylhydrazones of formula 9, can then be treated with an tertiary amine base in a polyhalogenated organic solvent, for example triethylamine or diisopropylethylamine, preferably triethylamine in a chlorinated hydrocarbon solvent, for example dichloromethane, to give the corresponding diazo esters of formula 11. This conversion is normally carried out at a temperature of between zero degrees and 40xc2x0 C., preferably at the ambient temperature.
Compounds of structure 12 where X is O may be prepared by reacting the diazo ester of formula 11 with the appropriate cycloalkyl, cycloalkenyl or non-aromatic heterocyclic alcohol in the presence of catalytic amount of rhodium (II) acetate. The reaction is conveniently carried in an inert solvent, preferably dichloromethane at a temperature of between zero degrees and 40xc2x0 C., preferably at room temperature.
In a like manner, compounds of structure 12, where X is S, may be prepared by reacting the diazo ester of formula 11 with the appropriate cycloalkyl, cycloalkenyl or non-aromatic heterocyclic mercaptan in the presence of catalytic amount of rhodium (II) acetate. The reaction is conveniently carried in an inert solvent, preferably dichloromethane at a temperature of between zero degrees and the reflux temperature of the mixture, preferably at the reflux temperature. 
Preparation of compounds of formula I where X is C(O) is outlined in Reaction Scheme I. More specifically, two related methods are utilized to prepare compounds of structure III, as shown in Reaction Scheme III, where X is C(O). In the first method, the phenylacetic acids of structure 3 are first converted to the corresponding ester 4 by any of the methods well known to those of normal competence in the field of organic chemistry. As an example, an acid of structure 3 in an inert solvent, for example methanol or diethyl ether or tetrahydrofuran or a mixture thereof, may be treated with an excess of an ethereal solution of diazomethane, or treatment of acid 3 with methanol in the presence of a catalytic amount of sulfuric acid.
The thus formed ester of structure 4 may be deprotonated by with a non-nucleophilic strong base, for example lithium diisopropylamide or lithium bis(trimethylsilyl)amide, in an inert solvent, for example diethyl ether or tetrahydrofuran, preferably tetrahydrofuran. The deprotonation reaction may be conveniently carried out in an inert atmosphere under anhydrous conditions at a temperature of from xe2x88x9250xc2x0 C. to xe2x88x92100xc2x0 C., preferably at xe2x88x9278xc2x0 C. The lithiated species formed in this manner, may be reacted in situ with a cycloalkyl or cycloalkenyl acid chloride of structure 19 while the reaction temperature may be maintained at a temperature of from xe2x88x9250xc2x0 C. to xe2x88x92100xc2x0 C., preferably at xe2x88x9278xc2x0 C. to give the compound of structure 12, where Xxe2x95x90C(O).
Cleavage of the alkali-labile ester moiety in compounds of structure 12 (Ra unbranched lower alkyl) may be carried out in accordance with known procedures. For example, the esters of structure 12, are treated with an alkali metal hydroxide, for example potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably potassium hydroxide in an inert solvent system, for example a mixture of ethanol and water. The saponification reaction may be generally performed at a temperature of from zero degrees to the reflux temperature of the mixture, preferably at room temperature, to furnish the acids of structure 14.
The coupling of carboxylic acids of structure 14 with the amines R6-NH2 (13) to give the amides of structure III can be performed by using methods well known to one of ordinary skill in the art. For example, the reaction may be conveniently carried out by treating the carboxylic acid of structure 14 with the amine 13 in the presence of a tertiary amine base, for example triethylamine or diethylisopropylamine and a coupling agent such as O-(1H-benzotriazo-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) or benzotriazol-1-yloxy(dimethylamino)phosphonium hexafluorophosphate (BOP). The reaction may be carried out in an inert solvent, such as a chlorinated hydrocarbon (e.g., dichloromethane) or N,N-dimethylformamide at a temperature between zero degrees and about room temperature, preferably at about room temperature, optionally in the presence of a substance that accelerates the rate of reaction, for example 1-hydroxybenzotriazole.
Alternatively, to prepare the amides of structure III, as shown in scheme III, the carboxylic acids of structure 3 can be activated through conversion to a mixed anhydride, which may be in turn reacted with the amine 13 in the presence of a catalyst to afford the amides of structure 18, or by using standard peptide coupling reagents such as HBTU. Subsequently the amide of structure 18 may be deprotonated by with a non-nucleophilic strong base, for example lithium diisopropylamide or lithium bis(trimethylsilyl)amide, in an inert solvent, for example diethyl ether or tetrahydrofuran, preferably tetrahydrofuran. The deprotonation reaction may be conveniently carried out in an inert atmosphere under anhydrous conditions at a temperature of from xe2x88x9250xc2x0 C. to xe2x88x92100xc2x0 C., preferably at xe2x88x9278xc2x0 C. The thus formed lithiated intermediate, may be reacted in situ with a cycloalkyl or cycloalkenyl acid chloride of structure 19 while the reaction temperature may be maintained at a temperature of from xe2x88x9250xc2x0 C. to xe2x88x92100xc2x0 C., preferably at xe2x88x9278xc2x0 C. to give the compound of structure III, where Xxe2x95x90C(O).
To produce the primary amides of structure 15, the carboxylic acids of structure 14 are converted to an activated species, preferably an acid chloride which in turn may be reacted with a protected form of ammonia, hexamethyldisilazane, to give after hydrolytic removal if the trimethylsilyl groups in situ, the primary amides. The carboxylic acids of structure 14 are transformed into the corresponding acid chlorides on treatment with oxalyl chloride in an inert solvent, such as a chlorinated hydrocarbon (e.g., dichloromethane) or an aromatic hydrocarbon such as benzene. The reaction may be carried out in the presence of a catalytic amount of N,N-dimethylformamide at a temperature of between zero degrees and about room temperature, preferably at about zero degrees. The subsequent reaction of the intermediate acid chloride with an excess of 1,1,1,3,3,3-hexamethyldisilazane may be carried out in situ at a temperature between zero degrees and about room temperature, preferably at about room temperature. Treatment of the formed bis(trimethylsilyl)amide with a large excess of methanol containing 5% sulfuric acid at room temperature provides the desilylated primary amide of structure 15.
The ureas of structure II are produced by three methods:
(a) reaction of the acid chlorides derived as described above from the carboxylic acids of structure 14 with a monosubstituted urea 16
(b) by reaction of the primary amide of structure 15 with and isocyanate of structure 17
(c) by reaction of esters of formula 12 (Ra=lower alkyl) with a monosubstituted urea (16) in the presence of an alkali metal alkoxide.
In the first mentioned procedure, the acid chloride, derived from the carboxylic acid of structure 14 on treatment with oxalyl chloride is as described above except the reaction may be run in fluorobenzene, may be reacted in situ with urea or a monosubstituted urea (16). The reaction may be carried out at a temperature between 50xc2x0 C. and about the reflux temperature of the mixture, preferably at about 70xc2x0 C. to yield the ureas of structure II. In the alternative scheme, the primary amide of structure 15 may be reacted with an isocyanate of structure 17, in an inert solvent such as an aromatic hydrocarbon, preferably toluene. The reaction may be normally carried out at a temperature between 50xc2x0 C. and about the reflux temperature of the mixture, preferably at the reflux temperature to yield the ureas of structure II.
For compounds of formula I where X is S, the thioethers of structure II and III (Xxe2x95x90S) may be converted to the sulfones of structure I (Xxe2x95x90SO2) by using methods well known to one of ordinary skill in the field of organic chemistry. For example, the transformation may be achieved by using a two-step procedure. In the first step, treatment of the thio ethers of structures II and III (Xxe2x95x90S) with an oxidizing agent, preferably sodium periodate in aqueous methanol furnished the intermediate sulfoxides of structure II and III (Xxe2x95x90SO). The reaction may be conveniently carried out at a temperature of between zero degrees and about room temperature, preferably at about room temperature. In the second step, treatment of the intermediate sulfoxides II and III (Xxe2x95x90SO) with an oxidizing agent, preferably potassium permanganate in aqueous methanol fumished the sulfones of structure I (Xxe2x95x90SO2). The reaction may be conveniently carried out at a temperature of between zero degrees and about room temperature, preferably at about room temperature.
The compound of formula I has an asymmetric carbon atom through which the group XR3 and the acid amide substituents are connected. In accordance with this invention, the preferred stereoconfiguration of this group is R, except in cases where X is carbonyl, where the preferred enantiomer is xe2x80x9cSxe2x80x9d. In cases wherein R3 is asymmetric (e.g. cycloalkene), an additional chiral center at the ring carbon connecting with atom xe2x80x98Xxe2x80x99 is generated. At this center, racemic compounds and compounds corresponding to both R and S configuration are part of this invention.
If it is desired to produce the R or the S isomer of the compound of formula I, this compound can be separated into these isomers by any conventional chemical means. Among the preferred chemical means is to react the compound of formula 14 (same as 14 above) with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula 14 is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula 14. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula 14 in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula 14 which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomer of formula I.
The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula 14 (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula 14 is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula 14 with a chiral alcohol, or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula 14 can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using any conventional method to hydrolyze an ester or an amide without racemization.
On the basis of their capability of activating glucokinase, the compounds of above formula I can be used as medicaments for the treatment of type II diabetes. Therefore, as mentioned earlier, medicaments containing a compound of formula I are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form, e.g. by combining a compound of formula I with a pharmaceutically acceptable carrier and/or adjuvant.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragees, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as an aerosol, for example in the form of a spray. For the preparation of tablets, coated tablets, dragees or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragees or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules. For the preparation of solutions and syrups, excipients that may be used include for example water, polyols, saccharose, invert sugar and glucose. For injectable solutions, excipients that may be used include for example water, alcohols, polyols, glycerine, and vegetable oils. For suppositories, and local or percutaneous application, excipients that may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols. The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents. It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Preferred forms of use are intravenous, intramuscular or oral administration, most preferred is oral administration. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, dosages of about 1-100 mg/kg body weight per day come into consideration.
All of the compounds described in the following syntheses activated glucokinase in vitro in accordance with the assay described in the Biological Activity Example.
This invention will be better understood from the following examples, which are for purposes of illustration and are not intended to limit the invention defined in the claims that follow thereafter.